Phosphatidylinositol 3-kinases participate in the regulation of numerous biological functions and have been directly implicated in the pathogensis of diabetes and cancer. Indeed, the PI3K family of enzymes is intimately involved in numerous cellular pathways spanning proliferation, survival, adhesion, movement, differentiation, membrane trafficking, glucose transport, neurite outgrowth, and superoxide production in cells. Many natural and synthetic inhibitors of PI3K's are known, for example, myricetin, quercetin, resveratrol, staurosporine, viridin, wortmannin, and liphagal (all shown below) but selective inhibition of an individual isoform is rare. As the human genome has numerous kinases, the selective inhibition of one isoform of PI3K, for example, PI3Kα (a lipid kinase isoform that holds a central role in several cancers), would be particularly beneficial. For instance, selective inhibitors of individual isoforms of these enzymes would allow for the targeting of specific diseases spanning cancer, cardiovascular disease, and autoimmune disorders.

Liphagal (the (+) enantiomer shown as compound 271 below), in the racemic form, has an IC50 of 100 nM against PI3Kα, and is at least 10-fold more potent against this isoform of the enzyme compared to any other PI3K, including the γ isoform. While other natural and synthetic inhibitors of PI3Ks are known, they do not show the same selective inhibition of the PI3Kαisoform as liphagal does in the racemic form, and they do not possess the same potency. For example, although the natural product wortmannin (compound 273 shown below) shows an IC50 of 12 nM toward PI3Kα, it has nearly equal potency against several other related enzymes. Additionally, quercitin (compound 274 shown below) and other molecules have been used in chemical genetics studies to understand the roles of certain PI3K's in cell signaling. Second generation synthetic molecules designed to mimic natural products (e.g., LY294002 (compound 275 shown below)) have also been developed and studied by the pharmaceutical industry. Though somewhat selective, molecules such as LY294002 (compound 275 shown below) lack the potency of liphagal (the (+) enantiomer shown as compound 271 below).

With its unique biological activity and potentially novel mode of action, liphagal shows promise in the development of new therapeutics and as a chemical tool for studying cellular signaling and disease states. Additionally, liphagal (in the racemic form) displays substantial cytotoxicity toward various cancer cell lines. Against LoVo (human colon) cells, liphagal (in the racemic form) displays an IC50 of 0.58 μM, and against another cell line, CaCo (human colon), liphagal (in the racemic form) displays an IC50 value of 0.67 μM. Also, liphagal (in the racemic form) shows some cytotoxicity toward the MDA-468 breast cancer line, i.e., and IC50 value of 1.58 μM.
From a structural perspective, liphagal is a tetracyclic meroterpenoid having an unprecedented [6-7-5-6] tetracyclic skeleton and has attracted significant attention from the synthetic organic community. While syntheses for the production of a racemic mixture of (±)-liphagal have been reported, no enantioselective method has been reported to date.